Scientific References
The research behind Metabolicum's evidence-based approach
How We Evaluate Evidence
Not all research is equal. We assign confidence grades to each source based on study design, sample size, replication status, and methodology. This helps you understand how confident you can be in each finding.
High Confidence
Replicated findings across multiple well-designed studies
Good Confidence
Well-designed single studies with strong methodology
Moderate Confidence
Observational data with consistent patterns
Emerging Evidence
Mechanistic or theoretical - interpret cautiously
Clinical Consensus
Practitioner experience without formal trials
Understanding the Reproducibility Crisis
Why are we so careful about evidence grading? Because a significant portion of published research fails to replicate.
| Study | Finding | Grade |
|---|---|---|
| Begley & Ellis, 2012 | Only 21% of landmark cancer studies could be replicated | A |
| Open Science Collaboration, 2015 | Only 36% of psychology studies replicated | A |
| Ioannidis, 2005 | Theoretical framework explaining why most findings are false | A |
This doesn't mean you should distrust all research. It means:
- •Single studies warrant caution — Replication matters
- •Peer review is necessary but not sufficient — Many peer-reviewed findings are later overturned
- •Effect size matters more than p-values — Statistical significance ≠ practical importance
- •Longer studies are generally more reliable — Short-term biomarker changes may not reflect long-term outcomes
We grade evidence honestly so you can calibrate your confidence appropriately.
Browse Citations
Showing 26 of 26 references
TG/HDL Ratio(7)
Gaziano JM, Hennekens CH, O'Donnell CJ, Breslow JL, Buring JE
Fasting triglycerides, high-density lipoprotein, and risk of myocardial infarction
Circulation
Key finding: TG/HDL ratio was the strongest predictor of myocardial infarction among all lipid measures examined
McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G
Use of metabolic markers to identify overweight individuals who are insulin resistant
Annals of Internal Medicine
Key finding: TG/HDL ratio ≥3.0 identified insulin-resistant individuals with 79% sensitivity and 65% specificity
McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters D, Simon J, Krauss RM
Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease?
American Journal of Cardiology
Key finding: TG/HDL ratio identified insulin resistance regardless of body weight
Hanak V, Munoz J, Teague J, Stanley A Jr, Bittner V
Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B
American Journal of Cardiology
Key finding: TG/HDL ratio of 3.8 predicted LDL phenotype B (small, dense) with 79% sensitivity and 81% specificity
Maruyama C, Imamura K, Teramoto T
Assessment of LDL particle size by triglyceride/HDL-cholesterol ratio in non-diabetic, healthy subjects without prominent hyperlipidemia
Journal of Atherosclerosis and Thrombosis
Key finding: TG/HDL ratio correlated with LDL particle size in healthy adults
Vega GL, Barlow CE, Grundy SM, Leonard D, DeFina LF
Triglyceride-to-high-density-lipoprotein-cholesterol ratio is an index of heart disease mortality and of incidence of type 2 diabetes mellitus in men
Journal of Investigative Medicine
Key finding: TG/HDL predicted both heart disease mortality and diabetes incidence
Salazar MR, Carbajal HA, Espeche WG, Aizpurúa M, Leiva Sisnieguez CE, et al.
Comparison of the abilities of the plasma triglyceride/high-density lipoprotein cholesterol ratio and the metabolic syndrome to identify insulin resistance
Diabetes & Vascular Disease Research
Key finding: TG/HDL ratio was better than metabolic syndrome criteria for identifying insulin resistance
HOMA-IR(4)
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC
Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man
Diabetologia
Key finding: Established HOMA-IR formula and validated against euglycemic clamp
Wallace TM, Levy JC, Matthews DR
Use and abuse of HOMA modeling
Diabetes Care
Key finding: Comprehensive review of HOMA validation and appropriate use
Stern SE, Williams K, Ferrannini E, DeFronzo RA, Bogardus C, Stern MP
Identification of individuals with insulin resistance using routine clinical measurements
Diabetes
Key finding: HOMA-IR ≥2.6 identified insulin resistance with 84% sensitivity
Gayoso-Diz P, Otero-González A, Rodriguez-Alvarez MX, Gude F, García F, et al.
Insulin resistance (HOMA-IR) cut-off values and the metabolic syndrome in a general adult population: effect of gender and age
BMC Endocrine Disorders
Key finding: Optimal HOMA-IR cutoffs vary by age and gender
Waist-to-Height(3)
Ashwell M, Hsieh SD
Six reasons why the waist-to-height ratio is a rapid and effective global indicator for health risks of obesity
International Journal of Food Sciences and Nutrition
Key finding: WHtR <0.5 as universal threshold across populations
Browning LM, Hsieh SD, Ashwell M
A systematic review of waist-to-height ratio as a screening tool for the prediction of cardiovascular disease and diabetes
Nutrition Research Reviews
Key finding: Systematic review confirming 0.5 threshold across 78 studies
Swainson MG, Batterham AM, Tsakirides C, Rutherford ZH, Hind K
Prediction of whole-body fat percentage and visceral adipose tissue mass from five anthropometric variables
PLoS One
Key finding: WHtR strongly predicts visceral fat (the metabolically harmful type)
Dietary Intervention(5)
Hallberg SJ, McKenzie AL, Williams PT, Bhanpuri NH, Peters AL, et al.
Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year
Diabetes Therapy
Key finding: TG/HDL ratio improved by 29%, HOMA-IR improved by 55%, HbA1c reduced from 7.6% to 6.3%
Athinarayanan SJ, Adams RN, Hallberg SJ, McKenzie AL, Bhanpuri NH, et al.
Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial
Frontiers in Endocrinology
Key finding: 2-year sustainability of metabolic improvements
Walton CM, Perry K, Hart RH, Berry SL, Bikman BT
Improvement in glycemic and lipid profiles in type 2 diabetics with a 90-day ketogenic diet
Journal of Diabetes Research
Key finding: TG/HDL improved from 4.7 to 1.9, HbA1c improved from 8.9% to 5.6%
Choi YJ, Jeon SM, Shin S
Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes: a meta-analysis of randomized controlled trials
Nutrients
Key finding: Significant TG reduction and HDL increase across 14 RCTs
Yuan X, Wang J, Yang S, Gao M, Cao L, Li X, Hong D, Tian S, Sun C
Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis
Nutrition & Diabetes
Key finding: TG decreased by 0.72 mmol/L, HDL increased by 0.14 mmol/L
Research Methodology(3)
Begley CG, Ellis LM
Drug development: Raise standards for preclinical cancer research
Nature
Key finding: Only 11 of 53 (21%) landmark cancer studies could be replicated
Ioannidis JPA
Why most published research findings are false
PLoS Medicine
Key finding: Theoretical and empirical argument that majority of research findings are false
Open Science Collaboration
Estimating the reproducibility of psychological science
Science
Key finding: Only 36% of psychology studies replicated
Lean Insulin Resistance(3)
Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S
The metabolically obese, normal-weight individual revisited
Diabetes
Key finding: Established MONW (metabolically obese normal weight) as clinical entity
St-Onge MP, Janssen I, Heymsfield SB
Metabolic syndrome in normal-weight Americans: new definition of the metabolically obese, normal-weight individual
Diabetes Care
Key finding: ~25% of normal-weight individuals have metabolic syndrome criteria
Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, et al.
The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering
Archives of Internal Medicine
Key finding: 23.5% of normal-weight adults were metabolically abnormal
LMHR Phenotype(1)
Feldman D, Bikman BT, Engel S, Wood RJ, Krebs JD, Norwitz NG
Lean mass hyper-responders: a new phenotype for low-carbohydrate diet adopters
Current Developments in Nutrition
Key finding: LMHR phenotype characterized by LDL >200, HDL >80, TG <70
How We Use References
In Calculators
Primary thresholds come from Grade A sources. When Grade A evidence suggests a range rather than a single value, we present the range with context.
In Educational Content
We draw on Grades A-C for educational claims, clearly labeling evidence quality. Grade D and E content is marked as theoretical or practitioner-derived.
In Paradigm Frameworks
- Standard Medical: Grade A (established guidelines)
- Research Consensus: Grade A-B (outcome research)
- Metabolic Optimization: Grade B-E (intervention research + clinical consensus)
Related Pages
Evidence Grades
Other Pages
This bibliography contains the research supporting Metabolicum's evidence-based approach.
Last comprehensive review: December 2025